This retrospective case-control study identified for the first time the factors related to the risk of in-hospital death in Critical COVID-19 patients at high risk of death, and proposed the warning value for reference. Our results show that comorbidity, lymphopenia, higher SOFA score, and critical classification were associated with higher rates of in-hospital mortality. In particular, lymphocyte count ≤ 0.8 × 109/L, SOFA score > 3, APACHE II score > 7, PaO2/FiO2 ≤ 200 mmHg, IL-6 > 120 pg/ml, and CRP > 52 mg/L were associated with an increased risk of 28-day and 60-day mortality, and shorter survival time in critical patients who had a more severe inflammatory reaction and organ dysfunction.
In this group of Critical COVID-19 cases, the rate of in-hospital death was 17%. Those who died had more serious inflammatory indicators and organ damage than survivors, a finding consistent with a recent research report on the characteristics of critical COVID-19 patients who died (9). In addition, nearly half of patients suffered a comorbidity, most commonly hypertension, followed by cardiovascular diseases and diabetes, very similar to characteristics of such patients in recent reports (10). Recently, a meta-analysis of 6 studies revealed that hypertension, diabetes, chronic obstructive pulmonary disease, cardiovascular disease, and cerebrovascular disease are related independent risk factors for death in patients with COVID-19 (11). A study involving 1,590 patients with COVID-19 showed that patients with two or more comorbidities had a significantly increased risk of poor prognosis compared to patients with no or only a single comorbidity (12). Previously, immune disorders and prolonged inflammation were posited to the key factors for adverse outcomes in COVID-19 patients, and patients with circulatory and endocrine system diseases are more likely to have immune cell dysfunction and prolonged inflammation (13).
Previous studies on SARS-COV infection have shown that lymphopenia has been helpful in predicting the severity and clinical outcome of SARS-COV infection, which may be due to the fact that lymphocytes are directly infected and destroyed by SARS-COV (14). Our study also found that, early in the disease course, non-survivors had significantly lower lymphocyte counts than did survivors, a result consistent with those of previous studies (15, 16). Previously, pathological results of patients who died showed that a large number of lymphocytes and monocytes had infiltrated into the lungs of these patients (17), and we found, through Kaplan-Meier curve analysis, that patients with lymphocytes < 0.8 had an increased risk of death.
The SOFA score is currently the most commonly used method of assessing multi-organ dysfunction in the world (18), predicting mortality in sepsis. SOFA score was likewise an independent risk factor for 60-day survival after admission in COVID-19 patients in our study. Patients infected with SARS-COV-2 who presented with the diagnostic criteria of sepsis were more likely to suffer from severe lung injury and even multiple organ dysfunction, which provides supporting evidence for the hypothesis proposed by the latest research (19). In this study, severe patients with infections and multiple organ dysfunction died mostly due to MODS at the end of the disease course. Considering that single organ failure is not the cause of death in COVID-19 patients, SOFA score can well predict the poor prognosis of patients, and the relevant Kaplan-Meier curve analysis of this study suggests that a SOFA score > 3 may indicate an increased risk of death for COVID-19 patients.
Based on Chinese Guidelines, patients are classified into severe and critical according to the severity of the disease. Patients classified as critical upon admission were at much greater risk of death, since such patients by definition have indications of a poor prognosis, including higher inflammatory indicators, more serious organ function damage, and higher SOFA score.
Inflammatory cytokines, such as IL-6, can cause the so-called "cytokine storm", which may be a driver of acute lung injury and ARDS, and promote the progression of tissue damage to multiple organ failure (20). In our subgroup analysis, IL-6 also was significantly increased in non-survivors, and the Kaplan-Meier curves showed that IL-6 > 120 pg/ml was associated with increased mortality. Our study also found a significantly different level of CRP between non-survivors and survivors, and previous studies have suggested that CRP level is an important indicator for diagnosing and evaluating severe pulmonary infectious diseases (21, 22). In the early stage of COVID-19 infection, the CRP level can reflect the pulmonary lesions and the severity of the disease, and our study found that CRP > 52 mg/L indicated a poor prognosis. Our study showed that the PaO2/FiO2 level was lower in critical patients than in severe patients, and PaO2/FiO2 ≤ 200 mmHg indicated a lower survival rate. SARS-COV-2 can attack the lung capillary endothelial cells, resulting in the exudation of a large amount of plasma components from the alveolar cavity, massive reduction in the number of lymphocytes and lymphocyte dysfunction, and infiltration of a large number of macrophages, further exacerbating lung injury (19). Additionally, APACHE II score is one of the indicators used to evaluate the criticality of patients in the ICU (23), and in our study an APACHE II score > 7 indicated a lower survival rate.
Our study has some limitations. Due to the retrospective study design and the small number of reported cases, not all laboratory tests were done in all patients, which may compromise the reliability of the statistical analysis. To verify the existing results, further research on an expanded sample size is compulsory.